A method to screen a wide variety of drug candidates without laborious purification steps could advance the fight against drug-resistant bacteria.
Efforts to combat the growing threat of drug-resistant bacteria are being supported by a new approach to streamlining the search for antimicrobial drug candidates, developed by researchers at Hokkaido University, led by Assistant Professor Kazuki Yamamoto and Professor Satoshi Ichikawa of the Faculty of Pharmaceutical Sciences. . Their methods, developed together with researchers elsewhere in Japan and the US, are discussed in an article in the journal Nature communication.
Antimicrobial resistance (AMR) in bacteria is a major and increasing challenge to healthcare worldwide, leaving doctors struggling to treat a wide range of serious and potentially fatal infections.
A promising target for new drugs against a variety of AMR bacteria is an enzyme embedded in bacterial cell membranes called phosphobacteria.N-acetylmuramoyl pentapeptide transferase (MraY). This enzyme catalyzes the formation of a specific lipid molecule called lipid I, which is essential for bacterial survival. Several inhibitors of MraY activity are already known, but improved versions are urgently needed.
“In this study, we used four known classes of MraY inhibitors that are used as antibiotics,” explains Yamamoto. “We have developed a drug discovery platform (in situ building library method) that combines a comprehensive synthesis method for natural product derivatives with direct evaluation of biological activity.”
The team split known inhibitors into MraY-binding regions (cores) and activity-modulating regions (accessories). From 7 cores and 98 accessories, they generated a library of 686 MraY inhibitor analogs. These analogs were tested against MraY and eight analogs were identified that possessed strong MraY inhibitory and antibacterial activity.
“After splitting the natural products, we attached aldehyde groups to the cores and hydrazine groups to the accessories. These groups react with each other to produce a hydrazone bond – allowing us to create the analog library in a simple way,” explains Yamamoto out.
The eight analogs were resynthesized into stable forms and their effectiveness was verified. Analog 2 had the highest effectiveness against drug-resistant strains, followed by analogs 3 and 6. Furthermore, analog 2 was effective in mouse infection models – a promising feature, as demonstrating efficacy in live animals is an important step toward developing successful new medicines.
Early indications also suggest that currently identified drug candidates have low toxicity against cells other than the target bacteria, raising hopes that they could lead to a range of antimicrobials that can be used safely in patients.
“We also demonstrated the broader potential of our drug discovery approach by applying it to identifying beneficial activity in the tubulin-binding natural products epothilone B, paclitaxel and vinblastine (anticancer drugs),” adds Ichikawa. “We were able to build a library of 588 analogs in just one month.”
By showing that their method can be applied to other types of drugs, the researchers have opened a significantly more general new avenue in drug development.
